Cesson Sevigne

Elritercept is an investigational therapeutic protein designed to increase red blood cell and platelet production by inhibiting the signaling of a subset of the transforming growth factor beta (TGF-ß) family of proteins to promote hematopoiesis. It is being developed for the treatment of low blood cell counts, or cytopenias including anemia and thrombocytopenia in participants with Myelodysplastic Syndrome (MDS) and Myelofibrosis (MF).

BACKGROUND Non-muscle infiltrating bladder tumors are a cancerous pathology with an estimated incidence of 13,000 new cases/year in France. ¾ of new cases are diagnosed at a stage where the cancer is of limited extension to the urothelial mucosa and/or its underlying chorion (non-muscle-invasive bladder cancer NMIBC). The management and follow-up of NMIBCs are performed according to the best practice recommendations issued by the Cancer Committee of the French Urology Association. The risk of recurrence at 1 and 5 years for NMIBC has been estimated in clinical trials to be between 15%-61% and 31%-78%, respectively, depending on grade, stage, number, size, frequency of previous recurrence and presence of carcinoma in situ. In this context, patients should have regular endoscopic examinations to ensure the absence of tumor lesions inside their bladder. Urine cytology pathology is recommended for the detection of recurrence of NMIBC. However, the negative predictive value of this examination does not allow it to be substituted for bladder endoscopy, as the risk of not recognizing a bladder tumor, especially of low grade, is too high. To date, no urinary biomarker has been shown to be clinically useful and their use is not recommended for the non-invasive detection of endovesical tumor recurrence. Urine sampling is recommended prior to bladder endoscopy for follow-up of NMIBC to ensure urine sterility (CBEU) and to perform urine cytology in patients with high-grade NMIBC and/or carcinoma in situ. The observational study of the clinical validity of the negative and positive predictive values of the biomarkers in a population of patients followed for a bladder tumor previously characterized is able to demonstrate the possibility of postponing the realization of the cystoscopy according to the tumoral characteristics and the treatments received by the patients. OBJECTIVES The main objective of the research will be to evaluate the diagnostic performance of biomarkers available in France, performed on a urine sample and providing a binary result (positive: probable presence of a tumor recurrence; negative: probable absence of a tumor recurrence) to the result of the bladder endoscopy performed as part of the routine care for the follow-up of NMIBC: determination of the negative and positive predictive values of biomarkers. The secondary objectives will be to describe the anatomopathological characteristics, the pathological history and the treatments received in the population, as well as analyze demographic and regional disparities in the treatment profiles of these diseases. MATERIAL AND METHOD When the patient is included in the study, medical data relating to the patient's pathology, including all previous treatments, will be entered into the register, as well as the name and result of the biomarker carried out before the resection (biopsy). At each follow-up endoscopic examination scheduled in the patient's personalized care plan, the investigating urologist will record its date and endoscopic findings (white light bladder fibroscopy). The name and result of the urine test will also be recorded by the urologist. The performance of the test will be evaluated from these data by calculating sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) and by means of an analysis of variance (ANOVA) to explore possible differences within the test by tumor grade and stage, and according to previous endovesical treatments received. The inclusion target is 8000 patients in France over a 3-year period.

Philadelphia-negative myeloproliferative neoplasms (MPN) are frequent and chronic myeloid malignancies including Polycythemia Vera (PV), essential thrombocythemia (ET), Primary Myelofibrosis (PMF) and Prefibrotic myelofibrosis (PreMF). These MPNs are caused by the acquisition of mutations affecting activation/proliferation pathways in hematopoietic stem cells. The principal mutations are JAK2V617F, calreticulin (CALR exon 9) and MPL W515. ET or MFP/PreMF patients who do not carry one of these three mutations are declared as triple-negative (3NEG) cases even if they are real MPN cases. These diseases are at high risk of thrombo-embolic complications and with high morbidity/mortality. This risk varies from 4 to 30% depending on MPN subtype and mutational status. In terms of therapy, all patients with MPNs should also take daily low-dose aspirin (LDA) as first antithrombotic drug, which is particularly efficient to reduce arterial but not venous events. Despite the association of a cytoreductive drug and LDA, thromboses still occur in 5-8% patients/year. All these situations have been explored in biological or clinical assays. All of them could increase the bleeding risk. We should look at different ways to reduce the thrombotic incidence: Direct Oral Anticoagulants (DOAC)? In the general population, in medical or surgical contexts, DOACs have demonstrated their efficiency to prevent or cure most of the venous or arterial thrombotic events. At the present time, DOAC can be used in cancer populations according to International Society on Thrombosis and Haemostasis (ISTH) recommendations, except in patients with cancer at high bleeding risk (gastro-intestinal or genito-urinary cancers). Unfortunately, in trials evaluating DOAC in cancer patients, most patients have solid rather than hematologic cancers (generally less than 10% of the patients, mostly lymphoma or myeloma). In cancer patients, DOAC are also highly efficient to reduce the incidence of thrombosis (-30 to 60%), but patients are exposed to a higher hemorrhagic risk, especially in digestive cancer patients. In the cancer population, pathophysiology of both thrombotic and hemorrhagic events may be quite different between solid cancers and MPN. If MPN patients are also considered to be cancer patients in many countries, the pathophysiology of thrombosis is quite specific (hyperviscosity, platelet abnormalities, clonality, specific cytokines…) and they are exposed to a lower risk of digestive hemorrhages. It is thus difficult to extend findings from the "general cancer population" to MPN patients. Unfortunately, only scarce, retrospective data regarding the use of DOAC in MPNs are available data. We were the first to publish a "real-life" study about the use, the impact, and the risks in this population. In this local retrospective study, 25 patients with MPN were treated with DOAC for a median time of 2.1 years. We observed only one thrombosis (4%) and three major hemorrhages (12%, after trauma or unprepared surgery). Furthermore, we have compared the benefit/risk balance compared to patients treated with LDA without difference. With the increasing evidences of efficacy and tolerance of DOAC in large cohorts of patients including cancer patients, with their proven efficacy on prevention of both arterial and venous thrombotic events and because of the absence of prospective trial using these drugs in MPN patients, we propose to study their potential benefit as primary thrombotic prevention in MPN.

This is a multinational, multi-center, observational, prospective, longitudinal disease registry designed to collect data on participants with cold agglutinin disease (CAD) or cold agglutinin syndrome (CAS). Among them, a minimum of 30 patients with CAD treated with sutimlimab are expected to take part in the sutimlimab cohort study. Patients with CAD who have been enrolled in previous sutimlimab clinical trials (e.g., BIVV009-01/LTS16214 \[NCT02502903,CAD patients\], BIVV009-03/EFC16215 \[NCT03347396\], and BIVV009-04/EFC16216 \[NCT03347422\]) and who either completed or discontinued the corresponding clinical trial are eligible to participate in the registry.

Part A of the trial=Dose-finding Study: Determination the optimal dose level in terms of both toxicity and efficacy for luspatercept + ESA Part B : Determination of the superiority and efficacy of the association Luspatercept+ESA (erythroipoiesis Stimulating Agent) over luspatercept alone in patients with lower risk MDS who failed to achieve a response or who subsequently relapsed after ESA, wihtout disease progression